Interleukin-1 (IL-1), tumor necrosis factor (TNF), and growth hormone releasing-hormone (GHRH) increase in non-rapid eye movement sleep (NREMS). The objective of this proposal is to advance our knowledge of the role cytokines/endocrines play in sleep regulation. We hypothesize that sleep factor (SF) IL-1, TNF and GHRH mediate NREMS responses to sleep deprivation, infection and T amb. Much data implicate IL-1, TNF and GHRH in NREMS regulation, e.g., exogenous IL-1, TNF or GHRH enhances NREMS in several species. Preliminary data also support this hypothesis, e.g., NREMS rebound after sleep deprivation is attenuated if animals are pretreated with anti-IL-1, anti-TNF or anti-GHRH. The specific aim of this proposal is to determine the levels of IL-1, TNF and GHRH in blood and specific brain regions after sleep deprivation, injection of microbial products and mild increases in Tamb. It is predicted that the levels of the putative SF will increase after each manipulation. The results will have a bearing on whether these SFs serve a physiological role in sleep regulation. At present, we know neither the functions, nor the exact cellular and molecular mechanisms responsible for sleep. The knowledge of the molecular causes of sleep is likely to be a necessary step toward our understanding of sleep function. The proposed research will provide information concerning normal sleep regulation, a variety of sleep disorders, cytokine/paracrine regulator mechanism, and interactions between the nervous and immune systems.